Human immunodeficiency virus type 1 infection of CD4+ T cells down-regulates the expression of CD28: effect on T cell activation and cytokine production.
ABSTRACT Infection with human immunodeficiency virus type 1 (HIV-1) results in dysregulation of normal T cell function. To study the effects of HIV-1 at the cellular level, primary T cell lines were generated by alloantigen stimulation of CD4+ T cells collected from peripheral blood of HIV-1-infected donors. Using Epstein-Barr virus-infected B lymphocytes (EBV-LCL) as a source of alloantigen, the T cell lines were expanded in vitro for 7 weeks. Uninfected T cell lines were cultured in parallel. Virus was inducible from the infected lines with stimulation, and complete infection was achieved after 4-7 weeks depending on the line. The down-modulation of CD28 expression correlated with virus replication and spread. Furthermore, CD28 mRNA was not inducible in the infected lines after stimulation with alloantigen. Loss of CD28 correlated with reduced responsiveness to costimulation with a monoclonal antibody to CD28 following similar engagement of the CD3 protein. In contrast, activation with alloantigen was not affected. HIV-1 infection and down-modulation of CD28 did not alter the relative levels of IL-2, IFN-gamma, and IL-4 mRNA. Production of the various cytokine mRNAs following alloantigen stimulation was inhibited by CTLA4Ig and thus remained under the regulation of CD80 and CD86 expressed on the EBV-LCL. Taken together, our data suggest that dysregulation of normal T cell function associated with HIV-1 infection may result in part form the loss of CD28 expression.
SourceAvailable from: Michael Schirmer[Show abstract] [Hide abstract]
ABSTRACT: CD4+CD28− T cells are a unique type of proinflammatory T cells characterised by blockade of costimulatory CD28 receptor expression at the transcriptional level, which is still reversible by IL-12. In healthy individuals older than 65 years, these cells may accumulate to up to 50% of total CD4+ T lymphocytes as in many immune-mediated diseases, immunodeficiency, and specific infectious diseases. Here we focus on CD4+CD28− T cells in chronic immune-mediated diseases, summarizing various phenotypic and functional characteristics, which vary depending on the underlying disease, disease activity, and concurrent treatment. CD4+CD28− T cells present as effector/memory cells with increased replicative history and oligoclonality but reduced apoptosis. As an alternative costimulatory signal instead of CD28, not only natural killer cell receptors and Toll-like receptors, but also CD47, CTLA-4, OX40, and 4-1BB have to be considered. The proinflammatory and cytotoxic capacities of these cells indicate an involvement in progression and maintenance of chronic immune-mediated disease. So far it has been shown that treatment with TNF-α blockers, abatacept, statins, and polyclonal antilymphocyte globulins (ATG) mediates reduction of the CD4+CD28− T cell level. The clinical relevance of targeting CD4+CD28− T cells as a therapeutic option has not been examined so far.Journal of Immunology Research 01/2015; 2015:1-11. DOI:10.1155/2015/348746 · 2.93 Impact Factor
Chapter: FIV as a Model for HIV: An Overview[Show abstract] [Hide abstract]
ABSTRACT: Animal models for human immunodeficiency virus (HIV) infection play a key role in understanding the pathogenesis of AIDS and the development of therapeutic agents and vaccines. As the only lentivirus that causes an immunodeficiency resembling that of HIV infection, in its natural host, feline immunodeficiency virus (FIV) has been a unique and powerful model for AIDS research. FIV was first described in 1987 by Niels Pedersen and co-workers as the causative agent for a fatal immunodeficiency syndrome observed in cats housed in a cattery in Petaluma, California. Since this landmark observation, multiple studies have shown that natural and experimental infection of cats with biological isolates of FIV produces an AIDS syndrome very similar in pathogenesis to that observed for human AIDS. FIV infection induces an acute viremia associated with Tcell alterations including depressed CD4 :CD8 T-cell ratios and CD4 T-cell depletion, peripheral lymphadenopathy, and neutropenia. In later stages of FIV infection, the host suffers from chronic persistent infections that are typically self-limiting in an immunocompetent host, as well as opportunistic infections, chronic diarrhea and wasting, blood dyscracias, significant CD4 T-cell depletion, neurologic disorders, and B-cell lymphomas. Importantly, chronic FIV infection induces a progressive lymphoid and CD4 T-cell depletion in the infected cat. The primary mode of natural FIV transmission appears to be blood-borne facilitated by fighting and biting. However, experimental infection through transmucosal routes (rectal and vaginal mucosa and perinatal) have been well documented for specific FIV isolates. Accordingly, FIV disease pathogenesis exhibits striking similarities to that described for HIV-1 infection.04/2007: pages 149-237;
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ABSTRACT: Objectives: To ascertain if immunization results in the restoration of responses to recall antigens, in the development of responses to presumed neoantigens, and to identify the virologic and immunologic correlates of these responses in persons with HIV-1 infection. Design and setting: Open-label study carried out at three university-affiliate AIDS Clinical Trials Units in the United States. Subjects and methods: Thirty-one subjects participating in AIDS Clinical Trials Group Protocol 375 who had received zidovudine, lamivudine, and ritonavir for at least 48 weeks. Subjects were immunized with tetanus toroid (TT) at entry and with inactivated hepatitis A vaccine (hep A) and keyhole limpet hemocyanin (KLH) at entry and 6 weeks. The development of antibody, lymphocyte proliferative assay (LPA), and delayed-type hypersensitivity (DTH) responses after immunization were monitored. Results: The LPA and DTH responses to TT improved in 57 and 68% of participants, respectively; 73 and 65% developed enhanced LPA and DTH responses to KLH. Forty-eight percent of patients developed a four-fold increase in antibody concentration to tetanus. Seventy-three percent of patients without detectable hepatitis A antibodies at baseline developed antibodies after, immunization. Eighty-three percent of patients experienced at least a four-fold rise in,KLH antibody concentration. Immune activation and viral load predicted poor recall responses and the number of memory CD4+ T-cells predicted good responses to recall antigens. Naive CD4+ T-cell numbers, decrease in viral load, increases in CD4+ and CD28+ cells, and decreases in immune activation were associated with responses to presumed neoantigens.AIDS 01/2000; 14(1):11-21. DOI:10.1097/00002030-200001070-00002 · 6.56 Impact Factor